A formidable challenge in the treatment of primary and metastatic brain cancers, especially in children, is the long-term neurocognitive deficiencies resulting from cranial irradiation (IR)-induced hippocampal neuronal apoptosis. Our laboratory has discovered a novel functional connection between the metabolic kinase GSK3? and the Non- homologous End-joining (NHEJ) pathway that repair DNA double-strand breaks (DSBs). Furthermore, our preliminary data revealed that the NHEJ mediator 53BP1 is directly phosphorylated by GSK3?; meanwhile, increased expression of the classic GSK3? substrate ?-catenin is associated with enhanced repair of IR-induced DSBs and survival in hippocampal neurons. Thus, we hypothesize that GSK3? regulates NHEJ-mediated repair of DSBs and determines neuron cytotoxicity following IR via suppression of 53BP1 and ?-catenin function. In addition, tumor cells which contain abnormal GSK3 ? activity will not exhibit GSK3?-mediated protection from IR-induced cytotoxicity. A series of in vitro and in vivo experiments are proposed to test our hypotheses: Aim 1 will identify the GSK3 ? phosphorylation sites in 53BP1 and determine whether GSK3 ? -specific phosphorylation direct 53BP1 function in NHEJ and in survival of irradiated hippocampal neurons. Aim 2 will determine whether GSK3 ? regulates 53BP1 through suppressing ? - catenin that may promote NHEJ activity by increasing 53BP1 transcription, or by directly interacts with 53BP1. Aim 3 will determine if abnormal GSK3 ? activity determine brain tumor cell resistance to the prophylactic GSK3 ? -inhibition mediated protection from radiation induced cytotoxicity.